surmountingchemotherapyandradioresistancein chondrosarcoma

Hindawi Publishing CorporationSarcomaVolume 2011, Article ID 381564, 8 pagesdoi:10.1155/2011/381564

Review Article

Surmounting Chemotherapy and Radioresistance inChondrosarcoma: Molecular Mechanisms andTherapeutic Targets

Anne C. Onishi, Alexander M. Hincker, and Francis Y. Lee

Department of Orthopaedics, College of Physicians and Surgeons, Columbia University, Black Building, 14-1412, 650 West 168th Street,New York, NY 10032, USA

Correspondence should be addressed to Francis Young-In Lee, [email protected]

Received 29 August 2010; Accepted 15 November 2010

Academic Editor: Alberto Pappo

Copyright © 2011 Anne C. Onishi et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Chondrosarcoma, a primary malignancy of bone, has eluded successful treatment with modern chemotherapeutic and radiationregimens. To date, surgical resection of these tumors remains the only curative treatment offered to patients with this diagnosis.Understanding and exploring the nature of chemotherapy and radiation resistance in chondrosarcoma could lead to newmolecular targets and more directed therapy for these notoriously difficult-to-treat tumors. Here we review the most currenthypotheses regarding the molecular mechanisms mediating chemotherapy and radiation resistance and the future direction ofchondrosarcoma therapy research.

1. “Know thy Enemy”: Treatment Obstacles inPatients with Chondrosarcoma

Tzu, the 6th century BC Chinese war theorist, is most famousfor his military treatise The Art of War and for havingwritten, “Know thyself, know thy enemy; one thousandbattles, one thousand victories” [1]. Chondrosarcoma, aheterogeneous group of tumors with extraordinarily diversepresentations and morphologies that have an enormousrange of clinical behaviors, is a complex and difficult enemyto know. To date, patients who receive a diagnosis ofchondrosarcoma are treated primarily with wide resectivesurgery since these tumors are notoriously resistant to bothchemotherapy and radiation treatment. Dramatic excisionsand even amputations are required, since local control oftumor is of paramount importance in order to prevent futuremetastasis.

Chondrosarcoma is the second most common typeof primary bone malignancy in the United States afterosteosarcoma. It represents 26% of all primary bone cancers,with approximately 2000 new cases every year [2]. These

tumors are characterized by cartilage-forming cells with noevidence of direct osteoid formation [3] and are gradedbased on local invasiveness and metastatic potential. Theycan be further classified by histologic characteristics suchas cellularity, matrix changes, cell character, and replicativeactivity [4]. Clinically, the most common sites of tumorformation include the pelvis and appendicular long bones,though reports in the literature have documented other sitesincluding the distal appendicular bones, temporomandibularregion [5], and thoracic spine [6].

While wide resection with limb salvage surgery or ampu-tation are definitive therapies for patients presenting withappendicular tumors [7], such surgeries introduce disabilityand morbidity into the lives of patients. Furthermore, suffi-ciently wide resection is not always possible in large tumors,tumors growing in the pelvis or axial skeleton, or tumorsthat have already metastasized. In such cases, tumor location,chemoresistance, and radioresistance lead to insurmountabletreatment obstacles and very poor outcomes. Understandingthe molecular mechanisms of resistance to chemotherapyand radiation in these tumors could lead to new targets

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for treatment or adjuvant therapies to surgery, therebyimproving the length and quality of life in patients sufferingfrom chondrosarcoma.

In this paper, we will provide a summary of the mostrecent research regarding the molecular pathways and genesresponsible for chemotherapy and radiation resistance inchondrosarcoma tumors (see Table 1). We will also explorethe implications of these molecular mechanisms with respectto their role in the development of new therapies for thisdifficult-to-treat cancer.

2. The Expression of P-GlycoproteinAllows Chondrosarcoma Cells toWithstand the Cytotoxic Effects ofMost Chemotherapy Agents

P-glycoprotein is an ATP-dependent membrane-boundpump that excretes small hydrophobic molecules and isnormally expressed in cells with secretory functions such asthe proximal tubular cells of the kidney and the epitheliallining of the bile duct. It is also expressed in the hypertrophicregion of the epiphyseal growth plate, providing additionalevidence for its important physiologic excretory roleinprotecting the cell from extracellular insults [8].

The expression of P-glycoprotein in chondrosarcomatumors has been well-established, and it has been proposedthat this expression is an extremely important mechanismin the development of chemoresistance (see Figure 1).P-glycoprotein is encoded by the gene Multiple DrugResistance-1, or MDR-1. Expression of this protein is com-mon in both benign and malignant cartilaginous lesions, andin one study, 90% of tumors stained with specific antibodieswere positive for P-glycoprotein expression [9]. The authorspostulated that MDR-1 expression was a marker for thepresence of drug resistance to multiple chemotherapy agentsincluding cyclophosphamide, doxorubicin, vincristine, cis-platin, methotrexate, and dacarbazine.

It has been shown using fluorescence microscopy andother in vitro techniques that chondrosarcomacells express-ing P-glycoprotein accumulate lower levels of intracellulardoxorubicin thanchondrosarcoma cells that do not expressP-glycoprotein, and that the P-glycoprotein-positive cellsare insensitive to the cytotoxic effects of doxorubicin atphysiologic concentrations in vitro [10]. Rosier et al. havepostulated that the development of chemoresistantchon-drosarcoma tumors is a result of selective pressure against P-glycoprotein-negative cells in the presence of cytotoxic agents[8]. Alternatively, some authors suggest that toxin exposurecauses direct upregulation of P-glycoprotein expression [13].

More recently, the importance of P-glycoprotein inmediating chemoresistance has been highlighted throughexperiments in which P-glycoprotein was inhibited bothpharmacologically and with gene silencing techniques. UsingsiRNA, Kim et al. showed that knocking down the expressionof MDR-1 increased chemosensitivity by up to 4.1 fold[12]. Of note, a combination of the inhibition of P-glycoprotein with the inhibition of the antiapoptotic proteins

Bcl-2, Bcl-xL, and XIAP showed an even higher increasein chemosensitivity, up to 5.5 fold [12]. These findingssuggest that though P-glycoprotein is clearly an importantmediator of chemoresistance in chondrosarcoma cells; othermechanisms are also involved.

3. Telomerase Activity MediatesChondrosarcoma Cell Immortality

DNA polymerase cannot faithfully complete replication tothe end of the superstructure of the macromolecule, whichleads to the loss of nucleotides with each replication cycle—this is known as the “end replication problem.” Telomeres areregions of noncoding DNA at the end of the double strandthat protect coding regions from this degradation. Withevery newgeneration, a piece of the telomere is lost, even-tually causing the cell to exit the replication cycle [14]. Germcells express telomerase, an enzyme capable of synthesizingnew telomeres via its own RNA template, thereby allowingtelomeres to be faithfully replicated and preventing the cellfrom exiting the replication cycle. Many cancer cell typesincluding testicular, ovarian, breast, endometrial, and basalcell carcinoma and lymphoma express telomerase, and this isone suggested mechanism of attaining cellular immortality[15].

Many chondrosarcoma cells also express telomerase,and it has been established that telomerase expression inchondrosarcoma correlates significantly with tumor gradeand rates of recurrence. Martin et al. have proposed thatusing immunohistochemical techniques to identify thosetumors that express telomerase could be a useful adjuvantto traditional prognostic grading systems [16]. Dr. Martin’sgroup has also explored the role of telomerase combinedwith the loss of tumor suppressor protein p16 as a means ofmalignant transformation of cartilage neoplasms and foundthat these two mutations in combination lead to a moreaggressive and invasive phenotype in vitro [17].

Because of the important relationship between telom-erase expression and cancer cell immortality, inhibition oftelomerase has been an expanding area of cancer therapyresearch. It is hypothesized that by preventing the continuedelongation of telomeres, malignant cells can reenter thenormal cell cycleand and undergo the normal genetic andmolecular checks on replication. Additionally, these cellswould become susceptible to the apoptotic mechanisms thatnormally execute the process of programmed cell death whengenetic damage is induced by chemotherapeutic agents.

The specific pharmacologic inhibitor of telomerase,BIBR1532, has been tested as a means to resensitize chon-drosarcoma cells to traditional modes of chemotherapy.Parsch et al. have established telomerase expression in thechondrosarcoma cell line SW1353 and used the TRAP assayto show that BIBR1532 inhibits telomerase in SW1353 cells.Furthermore, it was demonstrated that long-term dosageof the telomerase inhibitor slowed the rate of growthof SW1353 cells, but did not arrest growth completely;the authors contend that this incomplete growth arrest iscaused by chemotherapy-induced natural selection of clones

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Table 1: A summary of the mechanisms involved in chemotherapy and radiation resistance in chondrosarcoma cells. Summarized hereare the various molecular mechanisms responsible chemotherapy and radiation resistance in chondrosarcoma, strategies to overcome thesemechanisms, and the results of studies testing these strategies as possible adjuvants to traditional surgical treatments. See text for morein-depth discussions of each topic.

Resistancemechanism

Effect within the cell Therapeutic strategies Has treatment been tested?

P-glycoproteinexpression

Exports chemotherapydrugs from within thecell

Gene silencing using siRNA pharmacologicinhibition using C-4

In vitro: dramatic increases inchemosensitivity

Telomeraseactivity “Immortal” cell

phenotype

BIBR1532- pharmacological telomeraseinhibitor

BIBR152- in vitro: slowed growthand increased sensitivity tocisplatin.

GRN 163L- pharmacological telomeraseinhibitor

GRN 163L- in vivo: but not inchondrosarcoma—helpfuladdition in leukemia treatment

AngiogenesisSupports larger tumors,allows metastasis

SU6668-inhibits receptors for VEGF, FGF,PDGF ET-743 and plasminogen-relatedprotein B-chemotherapeutic andendothelial-cell-metabolism downregulator

In vivo murine model: decreasedtumor size, vascularization.

In vivo murine model:inductionof profound necrosis, inhibitionof neovascularization

COX-2expression

Unclear, but associatedwith poor prognosis

COX-2 inhibitors-mechanism of actionremains unclear

In vivo: slows cancer growth,although growth relapses aftersix weeks of treatment

Melovonatesynthesis

Shift bone remodelingbalance towardresorption

Bisphosphonates-inhibit melovonatesynthesis in the bone microenvironment

In vivo: induction of apoptosis,inhibition of metalloproteinaseactivity, and reduction of VEGFlevels

TumorSuppressor p16Mutation

Decreased tendencytoward apoptosis

p16-restoring virusOncolyticviruses-selectively target immune-inducingmolecules to cells with pathway defects

In vitro: increasedradiosensitivity in p16-deficientcells.

In vivo, but not inchondrosarcoma-results showstrong selectivity, desiredefficacy, no serious side effects.

Increasedexpression ofBcl-2, Bcl-xL, andXIAP

Decreased tendencytoward apoptosis

Downregulation viapharmacotherapy/siRNA-shift cellularbalance toward apoptosis

In vitro: increasedradiosensitivity

In vivo: increasedchemosensitivity

HypoxiaDecreased ROS creationby radiation

Acridine orange-enhances ROS creationIn vivo: significantly increasedradiosensitivity

with strong telomerase activity. Moreover, data from thisstudy show that cell lines with low-telomerase activity weremore sensitive to cisplatin-induced apoptosis while cell lineswith high levels of telomerase activity were nearly resistant[18].

In clinical trials, telomerase inhibition by the specificinhibitor GRN 163L has been shown to have additive oreven synergistic effects when used in combination with otherchemotherapies and radiation regimens against leukemia[19]. These promising clinical results taken together withthe aforementioned in vitro studies suggest that telomeraseinhibition may be a beneficial strategy in the treatment ofchemoresistant chondrosarcoma.

4. Targeting Angiogenesis inChondrosarcoma Slows Tumor Growth

One important area of cancer research has been the roleof angiogenesis in tumor growth and metastasis. As tumorsgrow beyond a few millimeters in size, oxygen can nolonger diffuse to every cell, and the tumor becomes hypoxic.Angiogenesis, or the growth of new blood vessels, mustoccur for the tumor to grow beyond a certain size. Hypoxiainduces angiogenesis via increased levels of the transcriptionfactor hypoxia inducible factor-1α (HIF-1α). This smallmoleculeactivates the transcription of several proangiogenicfactors, the most important of which is the cytokine vascular

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Geneticdamage

If repair mechanisms fail. . .

Apoptosis

Mediated by

Tumor suppressors

ChemotherapyRadiation

P-glycoprotein

Repair mechanisms fail, but. . .

SurvivalMediated by

p16 inactivating mutationsChondrosarcoma cell

Normal cell

Proapoptotic proteins

Antiapoptotic proteins

O2•−

Figure 1: An overview of how chondrosarcoma cells evade the cytotoxic effects of chemotherapy and radiation. In normal cells, radiationand chemotherapy cause cell death by inducing genetic damage either directly, or in the case of radiation, through a reactive oxygen species(ROS) intermediate. For example, the drug doxorubicin intercalates with DNA, preventing replication, while ROS cause strand breaks. Thisdamage is sensed by the cell, and then through the actions of tumor suppressor proteins such as p16 or p53 and the proapoptotic proteinsincluding Bax, Bak, and Bim, the cell undergoes apoptosis, becomes senescent, or necroses. The chondrosarcoma cell’s main defense againstchemotherapeutic agents is P-glycoprotein, a membrane-bound pump that extrudes small, hydrophobic molecules from within the cell[10]. The action of P-glycoprotein can lower intracellular concentrations of chemotherapeutic agents beyond a point at which they exacttheir cytotoxic effects. Though radiation treatment still induces genetic damage in chondrosarcoma cells, several mutations allow them tosurvive. These mutations include inactivation of the gene encoding the important tumor suppressor p16 via methylation or deletion [11],and upregulation of the antiapoptotic proteins Bcl-2 and XIAP [12]. Figure adapted from Motifolio Cell and Nucleic Acid Toolkit.

endothelial growth factor (VEGF). Because tumors dependon angiogenesis for survival and further growth, this pathwayhas become a popular drug target in many cancers, andchondrosarcoma is no exception.

Immunostaining and siRNA experiments have been usedto demonstrate that chondrosarcoma tumors of all gradesexpress HIF-1α at higher levels than do normal chondrocytesand benign cartilaginous tumors [20], and that VEGFexpression is dependent on HIF-1α [21]. Another studyconcluded that in chondrosarcoma, HIF-1α expression wasonly present in 40% of tumors sampled; however, this studywas unique in staining for nuclear HIF-1α, the active form.Tumors positive for nuclear HIF-1α were associated withdecreased disease-free survival, suggesting that nuclear HIF-1α could serve as a prognostic factor in addition to histologicgrade [20].

In terms of therapeutic potential, inhibiting angiogenesismay be a promising strategy for inducing growth arrest asan adjuvant to surgical removal of chondrosarcoma tumors.Klenke et al. have demonstrated that inhibition of the angio-genic tyrosine kinase receptors for VEGF, fibroblast growthfactor (FGF), and platelet-derived growth factor (PDGF)with the small-molecule inhibitor SU6668 has a beneficial

effect on tumor size and neovascular density in vivo. In thisstudy, mice with chondrosarcoma xenografts implanted inthe calvarium and treated with SU6668 had tumors thatwere 53% smaller than those tumors in mice treated withcontrol injections at the end of the 28 day growth period.Additionally, tumors in mice treated with the inhibitor hadvessel densities reduced by 37% compared to untreated mice[22]. In another in vivo xenograft model, ecteinascidin-743(ET-743), a sea squirt-derived chemotherapeutic, elicitedprofound tumor necrosis and prevented neovascularizationwhen used in combination with plasminogen-related proteinB, an endogenous molecule that downregulates endothelialcell metabolism [23].

5. Beyond Traditional Chemotherapy:Alternative Drug Targets inChemoresistant Chondrosarcoma

Though they present unique treatment obstacles, chon-drosarcoma tumors also present unique treatment oppor-tunities because they maintain many of the phenotypiccharacteristics of the chondrocytes from which they are

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derived. One interesting area of research involves treatingthese phenotypic similarities as drug targets. Some excitingexamples of these targets include cyclooxygenase-2 (COX-2)expression, melovonate synthesis, and estrogen signaling.

Chondrocytes are known to express the inflammatorycytokine COX-2 when exposed to other inflammatorycytokines and free radicals [24]. COX-2 expression has beendemonstrated in peripheral chondrosarcoma tumors inseveral studies, and higher levels of expression are associatedwith poor prognosis [25, 26]. Schrage et al. hypothesized thatthere may be a role for COX-2 inhibition in chondrosarcomatreatment. Dr. Schrage demonstrated that the COX-2inhibitor Celecoxib decreased cell viability in vitro. Celecoxibslowed tumor growth in vivo initially. Interestingly, thesemechanisms were independent of COX-2 activity sinceseveral cell lines showed these responses but did not expressCOX-2 according to ELISA assays [25]. Further study isneeded in this area because the in vivo growth arrest relapsedafter six weeks of treatment.

Like Celecoxib, bisphosphonates are typically used in thetreatment of other musculoskeletal conditions, but may haveindications in the treatment of chondrosarcoma. Bispho-sphonates inhibit melovonate synthesis and are extremelyspecific to the bone microenvironment. The mechanism ofaction involves inhibiting osteoclast-mediated bone resorp-tion and the promotion of osteoblast differentiation. Inter-estingly, bisphosphonates may have an anticancer effectby inducing apoptosis, inhibiting metalloproteinase activity,and reducing VEGF levels [27]. It has been shown thatthe bisphosphonate zoledronic acid acts synergistically withpaclitaxel in osteosarcomas [28]. In the context of chon-drosarcoma, one case report demonstrates that zoledronicacid significantly reduces bone pain and improves the qualityof life of patients with chondrosarcoma and chordoma [29].Furthermore, another study showed that the third generationbisphosphonate minodronate decreases chondrosarcoma cellgrowth in a dose-dependent manner in vitro [30].

Finally, the role of estrogen signaling in skeletal devel-opment has implications for chondrosarcoma treatment.Estrogen signaling is involved in longitudinal bone growth,chondrocyte differentiation, and epiphyseal growth platematuration. Therefore, Cleton-Jansen et al. hypothesizedthat targeting estrogen signaling could inhibit chondrosar-comacell proliferation. Dr. Cleton-Jansen demonstrated thatinhibiting estrogen signaling with the aromatase inhibitorexemestane inhibits chondrosarcoma cell growth in vitro[31]. Estrogen signaling has been an important target inother cancers such as breast carcinoma, and this studysuggests that it may also be an important target in chon-drosarcoma.

6. Radiation Resistance in Chondrosarcoma

Radiation treatment is used widely and commonly in cancertherapy and incites its cytotoxic effects via the productionof reactive oxygen species (ROS). These ROS then causestrand breaks in DNA. Under normal physiologic condi-tions, healthy cells have DNA repair machinery that senses

ROS-induced genetic damage and initiates attempts to repairthis damage (see Figure 1). If the damage is irreparable,proteins called tumor suppressors will signal to the cell tostop dividing and the cell will either undergo apoptosis,necrose, or become senescent. These mechanisms preventgenetic damage from being passed to future generations.

The efficacy of radiation treatment is contingent uponseveral things: first, formation of ROS is necessary tomediate genetic damage; second, the genetic damage-sensingmechanisms must be intact; third, the tumor suppressionactivity of the cell must be functional. Radiation resistance intumor cells could feasibly develop at any one of these threesteps due to mutations in the myriad proteins involved inthese complex cascades. The exact mechanisms of radiationresistance in chondrosarcoma have remained somewhatunclear, though several culprits, which will be reviewed here,have been identified.

7. Loss of Tumor Suppressorp16 in Chondrosarcoma Leads toRadioresistance

The role of the loss of tumor suppressor genes is one well-known cause of radioresistance in numerous tumors. Inchondrosarcoma, it has been shown that genetic changesto the p16 coding gene CDKN2 are quite common inhigh-grade tumors. Asp et al. have shown using PCRand gene sequencing that 41% of chondrosarcoma tumorssampled had some sort of change to CDKN2, while notumors sampled had any change to the well-known p53tumor suppressor gene [11]. In addition, almost all ofthe highly malignant tumors sampled had alterations tothis gene, suggesting that changes to the CDKN2 gene areone important mechanism contributing to high malignancy.Such mutations to p16 are not seen in benign cartilaginoustumors such as enchondroma, suggesting a role for thisgene in the transition to an aggressive, malignant phenotype[32]. These findings support evidence linking altered p16expression to malignant phenotypes in other types of cancerincluding breast carcinoma and oropharyngeal squamouscell carcinoma [33, 34].

The role of p16 in mediating radioresistance was demon-strated by experiments that showed that reintroducing p16expression with a viral vector can increase radiosensitivityin vitro by inciting mitotic catastrophe [35]. While nomethod of restoring the functionality of the p16 pathwayhas been developed in vivo, research is underway to use thedefective p16/retinoblastoma (RB) pathway as the markerfor targeting viral vectors to cancer cells. A virus couldtheoretically be derived that would only infect cells with adefect in the pathway; alternatively, a virus could be designedthat would infect indiscriminately but would only replicateand/or produce its immune-modulatory product in tumorcells [36].

Of course, treatments using viral vectors present theirown issues such as ensuring viral genomic stability and selec-tivity for cancer cells versus healthy cells. Early trials of theuse of such an oncolytic virus in the treatment of many types

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of cancer are currently underway. This particular adenovirusselectively targets cells with p16/RB pathway dysfunctionand stimulates the production of granulocyte-macrophagecolony-stimulating factor (GM-CSF), an immune modulatorthat locally induces CD8+ T cell and natural killer (NK)cell activity. Though the initial results suggest that the virusis capable of increasing tumor chemosensitivity withoutcausing severe side effects, these trials have not includedchondrosarcoma patients [37].

8. The Antiapoptotic ProteinsBcl-2, Bcl-xL, and XIAP Can MediateRadioresistance

Within any cell, survival and proliferation are mediated bya delicate balance between pro- and antiapoptotic signals.When the balance is tipped in favor of antiapoptotic signals,mediated by proteins such as Bcl-2, Bcl-xL, and XIAP, thecell will survive, proliferate, differentiate, and migrate. Con-versely, when the balance is tipped in favor of proapoptoticsignals, such as Bax, Bak, and Bim, the cell will exit the cellcycle, disrupt its nucleus, and begin to break apart into smallparts commonly referred to as “blebs.”

Given that ionizing radiation causes cytotoxicity byinducing apoptosis, one theory regarding radiation resis-tance is that some cancer cells may tip their own internalbalance to favor the anti-apoptosis signals. That way, nomatter how much genetic damage is induced by radiation,the cell will continue to differentiate, divide, and survive.

Kim et al. have shown that chondrosarcoma cells expresshigher basal levels of the antiapoptotic proteins Bcl-2 andXIAP than do normal chondrocytes in vitro, though thetwo cell types express similar amounts of the antiapoptoticprotein Bcl-xL [38]. In addition, radiation induces increasedexpression of these proteins in a dose-dependent manner,suggesting an important role of antiapoptotic signalingin radioresistance [38]. Finally, Dr. Kim demonstrated anincrease in radiosensitivity by using siRNA to silence theexpression of these proteins—silencing them individuallycould lead to up to 9.2 fold increases in radiation sensitivity.Silencing two of these genes simultaneously enhanced sensi-tivity to 5 and 10 Gy doses of radiation by 11.3 and 11.2 fold,respectively [38].

Clinically, gene silencing of Bcl-2 has great poten-tial as an adjuvant therapy. In Phase III trials, it hasalready been shown that the antisense oligonucleotideG3139 combined with the chemotherapy agent dacarbazineincreased progression-free and overall survival in patientswith advanced melanoma when compared to patients treatedwith just dacarbazine alone [39]. Such clinical studies haveshown that treating humans with antisense oligonucleotidesagainst Bcl-2 is feasible and potentially beneficial.

Little is known about the possible additive or synergisticeffects of Bcl-2 antisense oligonucleotides in the contextof radiation treatment, as no clinical trials have beenundertaken. Several studies have shown promising resultsin xenograft models: Bcl-2 antisense oligonucleotides haveinherent antitumor activity and can enhance the effects of

local tumor irradiation in a colon carcinoma model [40] andin a nasopharyngeal carcinoma model [41].

Given these findings, it would appear that targeting theexpression of these antiapoptotic proteins is a promising newavenue of inducing radiation sensitivity in chondrosarcomatumors. Previous clinical studies have already established thefeasibility and safety of antisense oligonucleotide treatmentand pharmacologic inhibition in humans, though in vivostudies in a chondrosarcoma model are lacking.

9. Technological Advancesin Radiation Therapy: ImprovingOutcomes in Chondrosarcoma

Many improvements in the field of radiation oncology ingeneral can be applied to treatment of chondrosarcoma. Inshort, these advances can be classified into those that allowthe delivery of greater amounts of radiation to the tumor andthose that enhance the killing power of a given amount ofradiation. With regard to the former category, improvementsin proton therapy have allowed the safe delivery of moreradiation to tumors. Unlike traditional radiotherapy, protontherapy does not deliver radiation to tissue beyond the tumor[42]. This is especially important in tumors occurring inareas such as the spine and the skull (tumors which aretraditionally very difficult to resect with a wide marginand, as such, most often in need of radiation). Additionaladvances in this technology have allowed increased focusingof the radiation (“spot-scanning” technology), allowing theuse of more intense radiation without increasing the toxicityto the patients. This technology was recently tested inchondrosarcomaof the skull base, and the results suggestthat the technique is relatively safe and can be an effectiveadjuvant to surgery when used at high doses [43].

In addition to delivering more radiation directly totumors, improving the efficiency of a given dose of radiationis another strategy for dealing with radioresistant tumors.Because of the hypoxic conditions inherent to the microen-vironment of a chondrosarcoma tumor, the generationof ROS is severely curtailed. Acridine Orange (AO) iscapable of producing damaging oxidants in the presence ofgamma radiation even in oxygen-poor environments. Thiscapability makes AO an attractive addition to radiotherapyfor chondrosarcoma. Moussavi-Harami et al. have shownthat AO in and of itself is only slightly cytotoxic but inducessignificant increases in sensitivity to low-dose radiation invitro [35].

10. Conclusion

We have reviewed here the numerous mechanisms thatmake chondrosarcoma a challenging cancer to treat. AsTzu suggested, knowing the enemy is a vital part of anysuccessful confrontation. Clinical experience has shown usthat chondrosarcoma is strongly resistant to traditionalmeans of cancer treatment, save for dramatic surgeries. YetTzu also notes that “the way to avoid what is strong is to strikeat what is weak” [1]. Cutting edge research in the field of

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chondrosarcoma has exposed some of these key weaknesses.Exploiting these vulnerabilities will allow us to underminethe resistance that has made these tumors such a frustratingclinical entity and to offer much needed treatment options topatients who would otherwise face a very poor prognosis.

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